US4292432A - Novel aldol derivatives and production thereof - Google Patents
Novel aldol derivatives and production thereof Download PDFInfo
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- US4292432A US4292432A US06/117,981 US11798180A US4292432A US 4292432 A US4292432 A US 4292432A US 11798180 A US11798180 A US 11798180A US 4292432 A US4292432 A US 4292432A
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- hydroxy
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- bicyclo
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- octane
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- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical class CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 title abstract description 17
- 238000004519 manufacturing process Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract 3
- -1 ethylenedioxy group Chemical group 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 5
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 10
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical class N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000000039 congener Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VYGFOIPPMMXQBI-AOOOYVTPSA-N (3ar,7as)-spiro[1,3,3a,4,7,7a-hexahydroindene-2,2'-1,3-dioxolane] Chemical compound O1CCOC11C[C@@H]2CC=CC[C@@H]2C1 VYGFOIPPMMXQBI-AOOOYVTPSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 238000006385 ozonation reaction Methods 0.000 description 2
- 150000003174 prostaglandin I2 derivatives Chemical class 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KMOUUZVZFBCRAM-OLQVQODUSA-N (3as,7ar)-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione Chemical compound C1C=CC[C@@H]2C(=O)OC(=O)[C@@H]21 KMOUUZVZFBCRAM-OLQVQODUSA-N 0.000 description 1
- LQZCYXCHWNQBKX-UHFFFAOYSA-N 1-dimethoxyphosphorylheptan-2-one Chemical compound CCCCCC(=O)CP(=O)(OC)OC LQZCYXCHWNQBKX-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/40—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/523—Saturated compounds containing a keto group being part of a ring containing —CHO groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to novel aldol derivatives which are very useful as intermediates for methanoprostacyclin derivatives, and a novel process for producing the same.
- PGI 2 which is shown below, inhibits aggregations of blood platelets and is expected to be useful for prevention of intravascular thrombosis, cerebrovascular thrombosis, and transient ischemic episodes.
- the starting material [II] was provided by oxidative cleavage of the olefin derivative [VI] as described below, which could be easily obtained from the industrially available, cis-4-cyclohexene-1,2-dicarboxylic anhydride by the known procedures [e.g. J.O.C. 41 2238 (1978)].
- the present invention has provided an efficient and advantageous synthesis of the methanoprostacyclin and it congeners.
- An object of the present invention is to provide the novel aldol derivative [I] which is useful as an intermediate for the production of the methanoprostacyclin and its congeners.
- Another object of this invention is to provide a novel and excellent synthetic method for producing the aldol derivative [I].
- Oxidation of the olefin derivative [VI] into the dialdehyde derivative [II] can be accomplished by treatment with sodium metaperiodate in the presence of a catalytic amount of osmium tetroxide in an inert solvent at a range of the temperature from 0° C. to room temperature.
- the inert solvent include water, ethers (e.g. dioxane, tetrahydrofuran) and aqueous ethers.
- the dialdehyde derivative [II] can be also obtained by ozonization at a range of temperature from -80° C. to -30° C., followed by reductive cleavage with dialkyl sulfide, triphenylphosphine, sodium bisulfite, zinc or the like, or by catalytic hydrogenation in the presence of palladium on charcoal.
- inert solvent for ozonization examples include alkanols (e.g. methanol, ethanol), halogenated hydrocarbons and ethers.
- Reduction of an ozonide may be accomplished by a, per se, conventional procedure at a range of temperature from -30° C. to room temperature.
- Aldol condensation of the dialdehyde [II] into the aldol derivative [I] is carried out in the presence of an acid or a base in an inert solvent such as water, alkanols, aqueous alkanols, ethers, and esters at a temperature ranging from -70° C. to room temperature.
- an inert solvent such as water, alkanols, aqueous alkanols, ethers, and esters
- alkali hydroxide e.g. potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide zinc hydroxide
- alkali carbonate alkali hydrogen carbonate and triethylamine
- mineral acids or organic acids examples of the suitable base.
- aldol derivative [I] are as follows:
- dialdehyde (1.0 g) obtained above (example 1 or 2) was dissolved in methanol (30 ml) and cooled at -15° ⁇ -5° C.
- dialdehyde (0.7 g) obtained above (example 1 or 2) was dissolved in methanol (17 ml). To this solution was added 5% aqueous barium hydroxide at 0° ⁇ 10° C.
- the alcohol obtained above was dissolved into a mixed solvent of acetic acid, water and tetrahydrofuran (3:1:1).
- the aqueous solution was washed with ether, acidified with aqueous potassium bisulfate and extracted with ethylacetate.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
A process for producing novel aldol derivatives of the formula, ##STR1## wherein C=W is a carbonyl group or a protected carbonyl group which comprises reacting a compound of the formula: ##STR2## wherein C=W is as defined above in the presence of an acid or a base at a temperature ranging from -70° C. to room temperature. The novel aldol derivatives of the above formula are useful as intermediate for producing methanoprostacyclin derivatives which are useful medicines for prevention of thrombosis.
Description
The present invention relates to novel aldol derivatives which are very useful as intermediates for methanoprostacyclin derivatives, and a novel process for producing the same.
The novel aldol derivatives provided by the present invention are those represented by the formula [I]: ##STR3## wherein C=W is a carbonyl group or a protected carbonyl group.
The novel process for producing the aldol derivatives [I] involves the intramolecular aldol cyclization of the dialdehyde derivatives of the formula: ##STR4## wherein C=W is as defined above.
A tremendous amount of research in synthetic organic chemistry, pharmacology and clinical application of prostaglandins has been performed since discovery of prostaglandins.
In 1976, J. Vane of the Wellcome foundation reported isolation and biological effect of prostacyclin [PGI2 ] (A) [(S. Moncada, R. Gryglewski, S. Bunting, and J. R. Vane, Nature (London), 263, 663 (1976)].
PGI2, which is shown below, inhibits aggregations of blood platelets and is expected to be useful for prevention of intravascular thrombosis, cerebrovascular thrombosis, and transient ischemic episodes.
However, PGI2 may not be used as a medicine owing to its instability. ##STR5##
In the course of our study seeking novel PGI2 analogs, the present inventors formed as novel PGI2 analogs, the methanoprostacyclin [B] and its congeners [Tetrahedron Letters, 2607 (1979)], which were found to have potent activities similar to PGI2. Moreover the methanoprostacyclin [B] and its congeners were found to be much more stable as compared with PGI2 itself, and thus, these novel methanoprostacyclin derivatives can be used as practically useful medicines for prevention of thrombosis, especially for prevention of platelet thrombosis induced by the use of prosthetic devices such as artificial heart valves. ##STR6##
As for the synthesis of the methanoprostacyclin [B], two other approaches have also been published from other research groups [Tetrahedron Letters, 433 (1979), J.C.S. Chemical Communications 1067 (1978), Tetrahedron Letters 3743 (1978)]. But, by any of the synthetic approaches stated above, the methanoprostacyclin [B] was very hard to prepare industrially, since the known syntheses were all suffering from some hardships (too many steps or low availability of the starting materials).
Thus, it has been strongly desired to develop more efficient and more advantageous synthetic approaches for the said methanoprostacyclin derivatives.
As the result of our study, the present inventors have found an efficient process for the synthesis of the aldol derivative [I], and the present inventors have also found that this aldol derivative [I] could be converted efficiently to the objective methanoprostacyclin [B] in only four steps without the protection of its hydroxyl group as shown in the following schema: ##STR7## wherein C=W is as defined above.
In the presebnt aldol cyclization of the dialdehyde derivative [II], the desirable one stereoisomer was obtained with good yields and high purity.
On the other hand, the starting material [II] was provided by oxidative cleavage of the olefin derivative [VI] as described below, which could be easily obtained from the industrially available, cis-4-cyclohexene-1,2-dicarboxylic anhydride by the known procedures [e.g. J.O.C. 41 2238 (1978)].
Thus, the present invention has provided an efficient and advantageous synthesis of the methanoprostacyclin and it congeners.
An object of the present invention is to provide the novel aldol derivative [I] which is useful as an intermediate for the production of the methanoprostacyclin and its congeners.
Another object of this invention is to provide a novel and excellent synthetic method for producing the aldol derivative [I].
According to the present invention, the aldol derivative [I] can be produced advantageously by reacting an olefin derivative of the formula: ##STR8## wherein C=W is a carbonyl group or a protected carbonyl group (e.g. W is an oxygen atom; ethylenedioxy group, an ethylendithio group, a 1,3-propane dioxy group, 2,2-dimethyl-1,3-propanedioxy group, a 1,2-phenylenedioxy group, two methoxy groups) with an oxidizing agent to give a dialdehyde derivative of the formula: ##STR9## wherein C=W is as defined above, followed by the intramolecular cyclization in the presence of an acid or a base.
The process of the present invention will be illustrated below in detail according to the sequence of the reaction steps.
Oxidation of the olefin derivative [VI] into the dialdehyde derivative [II] can be accomplished by treatment with sodium metaperiodate in the presence of a catalytic amount of osmium tetroxide in an inert solvent at a range of the temperature from 0° C. to room temperature. Examples of the inert solvent include water, ethers (e.g. dioxane, tetrahydrofuran) and aqueous ethers.
The dialdehyde derivative [II] can be also obtained by ozonization at a range of temperature from -80° C. to -30° C., followed by reductive cleavage with dialkyl sulfide, triphenylphosphine, sodium bisulfite, zinc or the like, or by catalytic hydrogenation in the presence of palladium on charcoal.
Examples of the inert solvent for ozonization include alkanols (e.g. methanol, ethanol), halogenated hydrocarbons and ethers.
Reduction of an ozonide may be accomplished by a, per se, conventional procedure at a range of temperature from -30° C. to room temperature.
Aldol condensation of the dialdehyde [II] into the aldol derivative [I] is carried out in the presence of an acid or a base in an inert solvent such as water, alkanols, aqueous alkanols, ethers, and esters at a temperature ranging from -70° C. to room temperature.
Examples of the suitable base are alkali hydroxide [e.g. potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide zinc hydroxide], alkali carbonate, alkali hydrogen carbonate and triethylamine, and as the acid, it is preferable to use mineral acids or organic acids.
Specific examples of the aldol derivative [I] are as follows:
2-β-formyl-3-α-hydroxy-7,7-ethylenedioxycis-bicyclo[3,3,0]octane
2-β-formyl-3-α-hydroxy-7,7-propanedioxycis-bicyclo[3,3,0]octane ##STR10##
2-β-formyl-3-α-hydroxy-7-oxo-cis-bicyclo[3,3,0]-octane
2-β-formyl-3-α-hydroxy-7,7-dimethoxy-cis-bicyclo[3,3,0]octane
2-β-formyl-3-α-hydroxy-7,7-ethylenedithiocis-bicyclo[3,3,0]octane
2-β-formyl-3-α-hydroxy-7,7-(2,2-dimethylpropanedioxy)-cis-bicyclo[3,3,0]octane ##STR11##
2-β-formyl-3α-hydroxy-7,7-phenylenedioxy-cis-bicyclo[3,3,0]octane
Practical and presently preferred embodiments of the invention are illustratively shown in the following examples without limiting the scope of the invention in any way.
A few milligrams of osmium tetraoxide were added to a solution of 8,8-ethylenedioxy-cis-bicyclo[4,3,0]non-3-ene (1.0 g), water (20 ml) and dioxane (60 ml).
The mixture was stirred for 5 min at room temperature, and to this mixture was added 2.2 g of sodium metaperiodate.
The mixture was further stirred for 20 min. at the same temperature. This reaction mixture was diluted with water and extracted with ether. The organic layer was washed with water, dried and evaporated under reduced pressure to give an oily cis-1,2-diformylmethyl-4,4-ethylenedioxy-cyclopentane.
IR νmax film ; 1725 cm-1
NMR δ(CDCl3); 3.8, 9.7 ppm
A solution of 8,8-ethylenedioxy-cis-bicyclo[4,3,0]non-3-ene (1.0 g) in methanol (50 ml) was cooled to -50° C. and subjected to a stream of ozonized oxygen. After the starting material had disappeared, 35 ml of dimethylsulfide was added and the mixture was stirred for 2 hr at -5°˜-15° C.
The mixture was then concentrated by introduction of a stream of nitrogen to give an oily cis-1,2-diformylmethyl-4,4-ethylenedioxy-cyclopentane.
The spectral data of the product coincided with that of example 1.
A solution of the cis-1,2-diformylmethyl-4,4-diethylenedioxy-cyclopentane (1.1 g) in methanol (30 ml) was cooled to -50° C. and treated with 5% aqueous potassium hydroxide, and further stirred at the same temperature. After 4 hr, a saturated solution of sodium chloride and ethylacetate was added to the mixture.
The organic layer was separated, washed with water, dried and concentrated under reduced pressure at a low temperature to give an oily 2-β-formyl-3-α-hydroxy-7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane as a main product.
IR νmax film ; 3400, 1710 cm-1
NMR δ(CDCl3); 3.85, 9.75 ppm
The dialdehyde (1.0 g) obtained above (example 1 or 2) was dissolved in methanol (30 ml) and cooled at -15°˜-5° C.
A 5% aqueous solution (10 ml) of potassium hydroxide was added, and the mixture was stirred for 13 min. at the same temperature.
The mixture was treated as shown in the example 3 to give an oily 2-β-formyl-3-α-hydroxy-7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane as a main product.
The dialdehyde (0.7 g) obtained above (example 1 or 2) was dissolved in methanol (17 ml). To this solution was added 5% aqueous barium hydroxide at 0°˜10° C.
After 1 hr at the same temperature, stirring was continued for 40 hr at a room temperature. The mixture was worked up as shown in example 3 or 4 to give an oily 2-β-formyl-3-α-hydroxy-7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane. The spectral data coincided with that of example 3 and there was much less content of the isomer.
A solution of 2-β-formyl-3-α-hydroxy-7,7-ethylenedioxy-bicyclo[3,3,0]octane (23.3 g) in tetrahydrofuran (30 ml) was added into a tetrahydrofuran solution of ylid prepared with dimethyl 2-oxoheptylphosphonate (29.1 g) and sodium hydride (65% mineral oil dispersion, 4.83 g) and the mixture was stirred for 2 hr at room temperature. Evaporation of the solvent gave an oily residue, to which ether and water was added. The ether layer was separated and dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel to give 2-β-(3'-oxo-trans-1'-octenyl)-3-α-hydroxy-7,7-ethylenedioxy-bicyclo[3,3,0]octane (19.9 g) as an oil.
IR νmax film ; 3400, 1670, 1630 cm-1
NMR δ(CDCl3); 6.68; 6.03; 3.83 ppm
A methanolic solution of 2β-(3'-oxo-trans-1'-octenyl)-3α-hydroxy-7,7-ethylenedioxy-bicyclo[3,3,0]octane (19.9 g) was treated with sodium borohydride (7.4 g) with ice cooling.
Stirring was continued for 2 hr and excess reducing agent was quenched with acetone, and then the mixture was concentrated under reduced pressure. To the residue was added aqueous ammonium chloride and extracted with ethylacetate.
The organic layer was dried and evaporated to give an oily 2β-(3'-hydroxy-trans-1'-octenyl)-3α-hydroxy-7,7-ethylenedioxy-bicyclo[3,3,0]octane (18 g).
The alcohol obtained above was dissolved into a mixed solvent of acetic acid, water and tetrahydrofuran (3:1:1).
The mixture was warmed at 45° C. and stirred for 4 hr. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel to give 2β-(3'β-hydroxy-trans-1'-octenyl)-3α-hydroxy-bicyclo[3,3,0]octane-7-one and 2β-(3'α-hydroxy-trans-1'-octenyl)-3α-hydroxy-bicyclo[3,3,0]octane-7-one.
3'β-hydroxy isomer
IR νmax film ; 3400, 1740 cm-1
NMR δ(CDCl3): 5.60, 0.9 ppm
3'α-hydroxy isomer
IR νmax film ; 3400, 1740 cm-1
NMR δ(CDCl3); 5.53; 0.9 ppm
A solution of sodium methylsulfinylmethide, prepared from 65% sodium hydride (1.86 g) and dimethylsulfoxide (30 ml), was cooled to 15°˜20° C. and treated with 4-carboxybutyl triphenylphosphonium bromide (11.23 g) under nitrogen.
The mixture was stirred for 10 min at 20° C. To the above ylid solution was added a dimethylsulfoxide solution of 2β-(3'α-hydroxy-trans-1'-octenyl)-3α-hydroxy-bicyclo[3,3,0]octa-7-one (0.84 g) at 20°˜25° C. The reaction mixture was stirred for 6 hr at room temperature, and then diluted with water.
The aqueous solution was washed with ether, acidified with aqueous potassium bisulfate and extracted with ethylacetate.
The extract was washed with brine, dried and concentrated in vacuo to give the residue (2.5 g). The residue was chromatographed on silica gel to give 2β-(3'α-hydroxy-trans-1'octenyl)-3α-hydroxy-7E-(4'-carboxybutylidene)-bicyclo[3,3,0]octane and 2β-(3'α-hydroxy-trans-1'-octenyl)-3α-hydroxy-7Z-(4'-carboxybutylidene)-bicyclo[3,3,0]octane.
7E isomer
IR δmax film ; 3350, 2650, 1710 cm-1
NMR δ(CDCl3); 5.65˜5.4 (2H), 5.1˜5.4 (1H), 4.6˜4.9 (3H)
7Z isomer
IR νmax film ; 3350, 2600, 1710 cm-1
NMR δ(CDCl3); 5.7˜5.45 (2H), 5.0˜5.4 (4H)
Claims (4)
1. A process for producing a compound of the formula: ##STR12## wherein C=W is a carbonyl group or a protected carbonyl group which comprises reacting a compound of the formula: ##STR13## wherein C=W is as defined above in the presence of an acid or a base at a temperature ranging from -70° C. to room temperature.
2. A process according to claim 1 wherein C=W is a protected carbonyl group.
3. A process according to claim 1 wherein the said base is an alkali hydroxide.
4. A process according to claim 1, wherein the protected carbonyl group is an ethylenedioxy group, an ethylenedithio group, a 1,3-propanedioxy group, a 2,2-dimethyl-1,3-propanedioxy group, a 1,2-phenylenedioxy group or two methoxy groups.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP1469079A JPS55105638A (en) | 1979-02-09 | 1979-02-09 | Aldol derivative and its preparation |
JP54/14690 | 1979-02-09 |
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US4292432A true US4292432A (en) | 1981-09-29 |
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US06/117,981 Expired - Lifetime US4292432A (en) | 1979-02-09 | 1980-02-04 | Novel aldol derivatives and production thereof |
Country Status (5)
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US (1) | US4292432A (en) |
EP (1) | EP0015653B1 (en) |
JP (1) | JPS55105638A (en) |
CA (1) | CA1142532A (en) |
DE (1) | DE3060152D1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1983004019A1 (en) * | 1982-05-06 | 1983-11-24 | Cbd Corporation | Cycloaliphatic pharmaceutical compounds |
WO1985002177A1 (en) * | 1983-11-08 | 1985-05-23 | Cbd Corporation | Halo bicyclo alkanones |
US4681951A (en) * | 1983-12-27 | 1987-07-21 | Sagami Chemical Research Center | Bicyclo(3.3.0)octene derivatives |
US4689345A (en) * | 1982-05-06 | 1987-08-25 | Cbd Corporation | Oxygenated alkyl substituted bicyclo alkanes |
US4689349A (en) * | 1982-05-06 | 1987-08-25 | Cbd Corporation | Anti-tumor halo bicyclo alkanones |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2040928B (en) * | 1978-01-26 | 1982-12-08 | Erba Farmitalia | Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres |
JPS58188850A (en) * | 1982-04-26 | 1983-11-04 | Sumitomo Chem Co Ltd | Novel bicyclooctane derivative and its preparation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US3338969A (en) * | 1963-02-27 | 1967-08-29 | Roussel Uclaf | A-nor-b-homo-estrane and process of preparation |
US4191660A (en) * | 1978-02-27 | 1980-03-04 | International Flavors & Fragrances Inc. | Organoleptic uses of 1-(3,3-dimethyl-2-norbornyl)-2-propanone in cationic, anionic and nonionic detergents and soaps |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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GB2040928B (en) * | 1978-01-26 | 1982-12-08 | Erba Farmitalia | Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres |
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1979
- 1979-02-09 JP JP1469079A patent/JPS55105638A/en active Granted
-
1980
- 1980-02-04 US US06/117,981 patent/US4292432A/en not_active Expired - Lifetime
- 1980-02-07 EP EP80300370A patent/EP0015653B1/en not_active Expired
- 1980-02-07 DE DE8080300370T patent/DE3060152D1/en not_active Expired
- 1980-02-08 CA CA000345313A patent/CA1142532A/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3338969A (en) * | 1963-02-27 | 1967-08-29 | Roussel Uclaf | A-nor-b-homo-estrane and process of preparation |
US4191660A (en) * | 1978-02-27 | 1980-03-04 | International Flavors & Fragrances Inc. | Organoleptic uses of 1-(3,3-dimethyl-2-norbornyl)-2-propanone in cationic, anionic and nonionic detergents and soaps |
Non-Patent Citations (9)
Title |
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Kojima et al., Tetrahedron Letters, pp. 3742-3747, 1978. * |
Konishi et al., Chemistry Letters, pp. 1437-1440, 1979. * |
Morton et al., J. Org. Chem., vol. 44, No. 16, 1979, 2880-2887. * |
Nicolaou et al., J.C.S. Chemical Communications, pp. 1067-1068, (1978). * |
Nielsen et al., Organic Reactions, vol. 16, p. 47. * |
Shibasaki et al., Chemistry Letters, pp. 1299-1300, 1979. * |
Shibasaki et al., Tetrahedron Letters, pp. 432-437, 1979. * |
Sugie et al., Tetrahedron Letters, pp. 2607-2610, 1979. * |
Wagner et al., Synthetic Organic Chemistry, p. 174 and p. 288. * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1983004019A1 (en) * | 1982-05-06 | 1983-11-24 | Cbd Corporation | Cycloaliphatic pharmaceutical compounds |
US4689345A (en) * | 1982-05-06 | 1987-08-25 | Cbd Corporation | Oxygenated alkyl substituted bicyclo alkanes |
US4689349A (en) * | 1982-05-06 | 1987-08-25 | Cbd Corporation | Anti-tumor halo bicyclo alkanones |
US4855322A (en) * | 1982-05-06 | 1989-08-08 | Cbd Corporation | Oxygenated alkyl substituted bicyclo alkanes |
WO1985002177A1 (en) * | 1983-11-08 | 1985-05-23 | Cbd Corporation | Halo bicyclo alkanones |
US4681951A (en) * | 1983-12-27 | 1987-07-21 | Sagami Chemical Research Center | Bicyclo(3.3.0)octene derivatives |
Also Published As
Publication number | Publication date |
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CA1142532A (en) | 1983-03-08 |
EP0015653A1 (en) | 1980-09-17 |
EP0015653B1 (en) | 1982-01-27 |
JPS6228140B2 (en) | 1987-06-18 |
JPS55105638A (en) | 1980-08-13 |
DE3060152D1 (en) | 1982-03-11 |
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